Role of the transcriptional regulator AP-2 in chondrocytes

• Applicant: Professorin Dr. Anja-Katrin Bosserhoff
• Subject Area: Pathology ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2010 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 163063400

Recently, we revealed protein expression of the transcription factor AP-2 epsilon in hypertrophic and articular cartilage tissue. Additionally, enhanced AP-2 epsilon mRNA expression in chondrocytes of osteoarthritis (OA) patients was determined. In the first funding period of this project two target genes of AP-2 epsilon in cartilage could be identified: CXCL1 as well as the gene for type II collagen. These data were published successfully in two scientific journals. In addition, we analyzed cartilaginous tissue samples of WT mice representing different stages of limb development for AP-2 epsilon expression. A strong induction of the expression level of the transcription factor was observed. A number of experiments provided evidence that hypoxia but not mechanical loading is a crucial external stimulus for this regulatory process. Currently, these data are submitted for publication. So far, analysis of embryonic cartilage and skeletal development in AP-2 epsilon deficient feti at various time points revealed no or just minor discrepancies to WT animals. This might be due to relatively low AP-2 epsilon expression in early embryonic cartilage structures and/or compensatory mechanisms.To determine the role of AP-2 epsilon in highly differentiated, articular cartilage as well as during osteoarthritis development and progression adult mice were subjected to an in vivo model for osteoarthritis. Here, the amount of damage to the articular cartilage surface was significantly increased in the AP-2 epsilon deficient animals 17 days after OA induction compared to the WT. Interestingly, activity of the matrix metalloproteinase Mmp13 was significantly enhanced in cartilage lacking AP-2 epsilon, offering a reasonable explanation for the abnormal disease progression observed in the knock-out mice. Within the renewal of this project the influence of AP-2 epsilon on the homeostasis of adult articular cartilage will be analyzed further. Of special interest is the molecular mechanism accounting for the observed Mmp13 dysregulation in AP-2 epsilon deficient mice. Another goal is to identify more genes that exhibit abnormal expression in articular cartilage of AP-2 epsilon knock-out specimen via microarray experiments. Additionally, a transgenic mouse model for AP-2 epsilon over-expression during early embryogenesis should provide valuable information about the role of the transcription factor during skeletal development. Furthermore, an in detail analysis of physiological AP-2 epsilon expression during embryonic development up to fully differentiated articular cartilage using an AP-2 epsilon promoter driven GFP mouse model is planned. Simultaneously, this model and corresponding in vitro experiments will be useful to identify additional potential factors regulating AP-2 epsilon expression next to hypoxia. The results of these experiments will contribute to the general understanding of chondrogenesis and pathogenic processes in articular cartilage.

• DFG Programme: Research Grants